The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
A variety of neurodegenerative diseases are characterized by neuronal cell loss. For example, a hallmark of Parkinson's diseases is the progressive loss of midbrain dopaminergic neurons, particularly in the A9 region of the substantia nigra. Other idiopathic and genetic neurodegenerative diseases include, for example, Huntington chorea, characterized by neuronal loss in the frontal lobes, caudate, and basal ganglia, and Alzheimer's disease, affecting the temporal and parietal lobes, the frontal cortex, and the cingulate gyrus.
The regenerative capacity of the adult brain is very limited. Mature neurons are believed to be post mitotic and there does not appear to be significant intrinsic regenerative capacity (i.e., from resident neural stem cells) in response to brain injury and neurodegenerative disease. Further, pharmacological interventions often become increasingly less effective as the susceptible neuronal populations are progressively lost.
Cell transplantation therapies have been used to treat neurodegenerative disease, with moderate success (e.g., Bjorklund et al., Nat. Neurosci. 3: 537-544, 2000). However, wide-spread application of cell-based therapies will depend upon the availability of large amounts of neuronal precursor cells having consistent characteristics. Preferably, the precursor cell populations will exclusively yield the therapeutic cell type, and cells that give rise to the deleterious effects potentially associated with cell transplantation therapies (e.g., neural tumors) are reduced or eliminated.
Neural cells differentiated in vitro from human embryonic stem cells (hESCs) or other pluripotent cell sources exhibit broad cellular heterogeneity with respect to developmental stage and lineage specification. Current differentiation protocols are able to enrich for particular cell subtypes; however, these protocols are not able to synchronize the birth and development of cell populations (Perrier et al., Proc. Natl. Acad. Sci. USA, 101: 12543-12548, 2004; Sonntag et al., Stem Cells, 25: 411-418, 2007; Yan et al., Stem Cells, 23: 781-790, 2005). Consequently, cells at different stages of maturation are present in the differentiated hESC cultures. Such heterogeneity may impede experimental, clinical, and therapeutic utilization of these cells.
The present invention provides compositions of neural cell populations derived from pluripotent stem cells, and methods for producing the same. The neural cell populations are provided as relatively homogeneous populations at defined stages of maturation and having defined characteristics.